The field of this invention is topical drugs for treating disease conditions of the skin or mucous membranes such as drugs for the treatment of psoriasis. The invention is particularly concerned with topical drugs which are administered in the form of prodrug compounds which are bioconvertible to the active drugs by enzymatic action.
In designing dermal targeting systems the improved absorption of the drug may require that its character be modified to an electronically neutral, non-ionic form so that it passes through the cell walls more readily. Further, lipophilic forms of such drugs are in general more readily absorbed into the dermal or epidermal cells. When the active drug itself is a charged moiety in aqueous solution and/or is inadequately lipophilic, it has been proposed to modify the drug to a prodrug form having these characteristics. For effective action after absorption, however, such prodrugs must be converted to the active drug within the target cells, but very little is known about the required chemical structure for such topical bioavailability.
Another problem which is encountered with respect to topical drugs is that the active form may have a serious toxic side effect if present in the circulatory system in significant concentrations. For example, it is known that the drug 6-aminonicotinamide (6-AN) is more effective against psoriasis than methotrexate but that it requires greater care in use. It has been shown that unless topical applications of 6-AN are accompanied by oral nicotinamide, a central nervous system toxicity (CNS) may result (Zackheim (1975) Arch. of Derm. 111: 880-882; and Zackheim (1978) Arch. of Derm. 114: 1632-1638.). 6-AN has also been shown to have anti-cancer activity but its use is questionable due to the CNS side effects (Ross (1967) Biochemical Pharm. 16: 675-680; Miyasaka et al (1975) J. Pharm. Soc. Japan 95: 547-551.). For treatment of psoriasis or skin cancer, it would be desirable to administer 6-AN in the form of a prodrug to permit uptake by cells while reducing its systemic toxicity.
U.S. Pat. No. 4,258,052 discloses various chemical analogues of 6-AN including substituents on the 6-amino group. In some of these the amino group of the side chain has been converted to an amide group which connects to an aliphatic group terminating in an ester group. For example, such compounds include the methyl and ethyl esters of 6-succinylamino nicotinamide.